This invention relates to a process for the production of 3-(17.beta.-hydroxy-4-androsten-3-on-17.alpha.-yl)-propionic acid lactone.
Various processes for the preparation of 3-(17.beta.-hydroxy-4-androsten-3-on-17.alpha.-yl)-propiolactone are known. Thus, for example, Arth et al., J. Med. Chem. 6 (1963) 617, condense 3.beta.-hydroxy-17-ketoandrost-5-ene with a Grignard reagent from the tetrahydropyranyl ether of propargyl alcohol to obtain the 17.alpha.-[3-(2-tetrahydropyranyloxy)-propinyl]-5-androstene-3.beta.,17-di ol, which is then hydrogenated to the 17.alpha.-[3-(2-tetrahydropyranyloxy)-propyl]-5-androstene-3.beta.,17-diol . After Oppenauer oxidation and subsequent ether splitting, 17.alpha.-(3-hydroxypropyl)-4-androsten-17.beta.-ol-3-one is obtained from which, by ring closure reaction with p-tolylsulfonic acid chloride and oxidation by chromic acid/pyridine, the above-mentioned propiolactone is produced.
Another mode of operation is described by Cella et al., J. Org. Chem 24 (1959) 743, also starting with the 3-hydroxy compound. In this process, 3.beta.-hydroxy-5-androsten-17-one is ethinylated, the 17.alpha.-ethinyl product is reacted with carbon dioxide to form the 17.alpha.-ethinyl-carboxylic acid, which is then reduced with hydrogen to the 17.alpha.-ethenyl-carboxylic acid. By acid treatment, the 3-(3.beta.,17.beta.-dihydroxy-5-androsten-17.alpha.-yl)-propenoic acid lactone is obtained which is hydrogenated to the saturated lactone, 3-(3.beta. ,17.beta.-dihydroxy-5-androsten-17.alpha.-yl)-propiolactone. An Oppenauer oxidation follows this reaction, leading to the desired 3-(17.beta.-hydroxy-4-androsten-3-on-17.alpha.-yl)-propiolactone.
However, all of these methods have the disadvantage that they involve a rather large number of reaction stages.
The invention is directed to a simpler process for the production of the above-mentioned lactone, starting with 1,4-androstadiene-3,17-dione or 4-androstene-3,17-dione, respectively, requiring a fewer number of reaction stages.